Antibodies (or Immunoglobulins, Igs) are proteins produced by the immune system in response to the presence of a foreign substance in the body. Immunoglobulins also serve and mediate other functions of the immune system. The nucleic acid sequences that encode immunoglobulins are initially derived from several genes in the genome (germline), which are subsequently rearranged and mutated during maturation to further increase the diversity of the immunoglobulins in their final, mature form. IgG, a typical immunoglobulin, has a Y-shaped structure formed by four chains: two heavy and two light chains, each with a variable and constant region. The variable regions can be further divided into various subregions, such as the framework (FR) and complementarity-determining regions (CDRs).
Immunoglobulins have been used to treat various diseases and conditions, for example allergies, transplant rejection, cancer, and host-versus-graft disease. However, when administering therapeutic antibody preparations to human patients, the antibodies sometimes provoke an undesired and potentially dangerous immune response by the patient to the antibodies themselves (“immunogenicity”), especially after repeated administrations. Immunogenicity can pose a particular problem when the antibody is from a nonhuman source, such as from an animal. When the antibody is derived from mouse, as is frequently used in therapeutic models, the patient may develop a human anti-murine antibody (HAMA) response. To reduce undesired immunogenicity such as HAMA, certain regions of an animal antibody can be replaced with corresponding regions of human antibodies, in essence “humanizing” the antibody. Modified antibodies, such as “chimeric” antibodies and CDR-grafted antibodies, have been developed to reduce immunogenic responses. However, such replacement strategies may not sufficiently minimize immunogenicity and can reduce the therapeutic efficacy of the immunoglobulin. Thus, there is a need for modified immunoglobulins that reduce or eliminate immunogenicity while maintaining or even improving therapeutic efficacy.